It has been desired to develop an effective therapy for diseases with chronic pancreatitis, and it is efficient in a development process for such a therapy to use a model animal that develops chronic pancreatitis.
Pancreatitis is thought to be caused by unbalance between an activity of trypsin produced in pancreas and an activity of an inhibitor that inhibits the activity of the trypsin.
That is, when the activity of the trypsin is relatively higher than the activity of the inhibitor or when the activity of the inhibitor is relatively lower than the activity of the trypsin, the pancreatitis is caused.
Thus, as a model animal that develops the pancreatitis, a model animal modified to express excessively tripsinogen has been produced by injecting a transcription gene constructed using fragments each encoding an esterase promoter as well as a polyadenylation site of pancreatic tripsinogen, β-globin and an SV40 from a wild mouse into a pronucleus of a C57B1/6 mouse fertilized egg (see Herbert Archer et al., A mouse model of hereditary pancreatitis generated by transgenic expression of R122H tripsinogen, Gastroenterology, 2006, Vol. 131, p 1844-1855).
However, the model mouse produced by such conventional methods was problematic in that loss of pancreatic gland cells and fibrosis of pancreas which were characteristic observations for human chronic pancreatitis were not observed. That is, no model mouse for the chronic pancreatitis can be produced by the aforementioned conventional method.
Thus the present inventors produced knockout mice in which a Spink 3 (serine protease inhibitor Kazal type 3) gene that is a mouse homolog for human Spink 1 (serine protease inhibitor Kazal type 1) had been knocked out (see Masaki Ohmuraya et al., Autophagic cell death of pancreatic acinar cell in serine protease inhibitor Kazal type 3-deficient mice, Gastroenterology, 2005, Vol. 129, p 696-705)